Activation of neu by missense point mutation in the transmembrane domain in schwannomas induced in C3H/HeNCr mice by transplacental exposure to N-nitrosoethylurea

Transplacentally initiated schwannomas in mice and rats arise preferentiall y in the Gasserian ganglion of the trigeminal nerve and spinal root ganglia , while those of the Syrian golden hamster most commonly occur subcutaneous ly. Rat and hamster schwannomas almost invariably contain a mutationally ac tivated neu oncogene. In rat schwannomas, the mutant allele predominates, w hile the relative abundance of mutant alleles is very low in hamster nerve tumors. We investigated whether neu is mutated in mouse schwannomas and whe ther the pattern and allelic ratio of the mutation resemble those for the h amster or the rat, Pregnant C3H/HeNCr mice received 0.4 mu mol N-nitrosoeth ylurea/g body weight on day 19 of gestation. Ten trigeminal and one periphe ral nerve schwannomas developed in II of the 201 offspring. Missense T --> A transversion mutations were detected in the neu transmembrane domain in e ight of ten schwannomas analyzed, as determined by MnlI digestion of polyme rase chain reaction products. The mutant allele was pre dominantly detected in two tumors and was abundant in six others. Transfection of eight out of ten mouse tumor DNAs into hamster cells yielded transformed foci; seven ou t of eight contained mutant mouse neu. Mouse schwannomas closely resembled those of rats both in the preferred anatomical site and in the mutant/wild- type neu allele ratios.